bosentan
Pharmaranks rates Bosentan 3.3/5 for recall safety — an independent score from its FDA recall history and its manufacturer's record. Bosentan is an endothelin receptor antagonist used to treat Pulmonary Hypertension.
Endothelin Receptor Antagonist · by Zydus Pharms USA Inc
Generic of Tracleer
Based on 1 source · Recall-safety score from FDA recall history — this product's own recalls and its manufacturer's record. Not an efficacy or quality rating. methodology →
Key facts
- Active ingredient
- Bosentan
- Drug class
- Endothelin Receptor Antagonist
- Form
- Tablet
- Strength
- Bosentan 32MG
- Type
- Prescription (Rx)
- Brand or generic
- Generic
- May treat
- pulmonary hypertension
- Manufacturer
- Zydus Pharms USA Inc
- FDA application
- ANDA213981
- FDA boxed warning
- Yes — see the boxed warning
What is Bosentan?
From the FDA label:Bosentan tablets for oral suspension is an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2´]-bipyrimidin -4-yl]-benzenesulfonamide monohydrate and has the following structural formula: Bosentan has a molecular weight of 569.63 and a molecular formula of C 27 H 29 N 5 O 6 S.H 2 O. Bosentan is a white to yellowish powder. It is soluble in acetonitrile, slightly soluble in methanol and practically insoluble in water. In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive. Bosentan is available as a 32 mg tablet for oral suspension and contains the following excipients: acesulfame potassium, aspartame, basic butylated methacrylate copolymer, colloidal silicon dioxide, corn starch, croscarmellose sodium, magnesium stearate, mannitol, sodium lauryl sulfate, stearic acid, talcum and tutti frutti flavor. Each dispersible tablet contains 2.08 mg of phenylalanine. Each dispersible tablet contains 33.045 mg of bosentan monohydrate, equivalent to 32 mg anhydrous bosentan. Image
How to use
Patients older than 12 years of age: initiate at 62.5 mg orally twice daily; for patients weighing greater than 40 kg, increase to 125 mg orally twice daily after 4 weeks (2.2). Patients 12 years of age and younger: dosage is based on weight, see Table 1 ( 2.2 ). Reduce the dose and closely monitor patients developing aminotransferase elevations more than 3 X Upper Limit of Normal (ULN) ( 2.1 ). 2.1 Required Monitoring Healthcare professionals who prescribe bosentan must enroll in the Bosentan REMS and must comply with the required monitoring to minimize the risks associated with bosentan [see Warnings and Precautions ( 5.2 )] . Measure liver aminotransferase levels prior to initiation of treatment and then monthly [see Boxed Warning, Warnings and Precautions ( 5.1 , 5.2 )]. Exclude pregnancy before initiating treatment with bosentan in females of reproductive potential [see Boxed Warning, Contraindications ( 4.1 ), Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 , 8.3 )] . 2.2 Recommended Dosage Administer bosentan orally following the dosing recommendations in Table 1. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity. Table 1 Dosing Recommendations Initial 4 weeks Maintenance (after 4 weeks) Patients > 12 years of age and > 40 kg 62.5 mg twice daily 125 mg twice daily…
Side effects
The following important adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Boxed Warning, Warnings and Precautions ( 5.1 )] Embryo-fetal Toxicity [see Boxed Warning, Warnings and Precautions ( 5.3 )] Fluid Retention [see Warnings and Precautions ( 5.4 )] Common adverse reactions (≥ 3% more than placebo) for the film- coated tablet are respiratory tract infection and anemia (6.1). Common adverse reactions (≥ 15%) for the dispersible tablet are upper respiratory tract infections and pyrexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety data on bosentan were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 adult patients with PAH and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to bosentan in these trials ranged from 1 day to 4.1 years (n=94 for 1 year; n=61 for 1.5 years; and n=39 for more than 2 years).…
FDA Boxed Warning (the FDA’s most serious warning)
Boxed (black-box) warning — from the FDA label
RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY Because of the risk of hepatotoxicity, bosentan is available only through a restricted program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS). Under the Bosentan REMS, prescribers, patients and pharmacies must enroll in the program [see Warnings and Precautions ( 5.2 )] . Hepatotoxicity In clinical studies, bosentan caused at least 3-fold upper limit of normal (ULN) elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.1 )] . In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with bosentan in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of bosentan in these cases could not be excluded. In at least one case, the initial presentation (after > 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of bosentan. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping bosentan with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration ( 2.4 )] . Elevations in aminotransferases require close attention [see Dosage and Administration ( 2.4 )] . Bosentan should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, treatment with bosentan should be stopped. There is no experience with the reintroduction of bosentan in these circumstances. Embryo-Fetal Toxicity Bosentan is contraindicated for use during pregnancy because it may cause fetal harm if used by pregnant females based on animal data. Therefore, for females of reproductive potential, exclude pregnancy before the start of treatment with bosentan. Advise use of effective contraception before initiation, during treatment and for one month after stopping bosentan. When pregnancy is detected, discontinue bosentan as soon as possible [see Dosage and Administration ( 2.1 ), Contraindications ( 4.1 ), Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.2 ), Use in Specific Populations ( 8.1 , 8.3 )]. WARNING: RISKS OF HEPATOTOXICITY and EMBRYO -FETAL TOXICITY See full prescribing information for complete boxed warning. Bosentan is available only through a restricted distribution program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS) because of the risks of hepatotoxicity ( 5.2 ): Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with bosentan ( 5.1 ). Measure liver aminotransferases prior to initiation of treatment and then monthly ( 2.1 , 5.1 ). Discontinue bosentan if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥ 2 x ULN ( 2.4 , 5.1 ). Based on animal data, bosentan may cause fetal harm if used during pregnancy ( 4.1 , 5.3 , 8.1 ). Females of reproductive potential: Exclude pregnancy before initiating treatment. Use effective contraception prior to initiation of treatment, during treatment and for one month after stopping bosentan ( 2.1 , 4.1 , 5.3 , 8.1 , 8.3 ). When pregnancy is detected, discontinue bosentan as soon as possible ( 5.3 ).
Warnings
Important safety information
Fluid retention: May require intervention ( 5.4 ). Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing bosentan ( 5.5 ). Decreased sperm counts ( 5.6 ). Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter ( 5.7 ). 5.1 Hepatotoxicity ALT or AST > 3 x ULN were observed in 11% of bosentan-treated patients (n=658) compared to 2% of placebo-treated patients (n=280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥ 3 x ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan. In a pooled analysis of four pediatric studies conducted in PAH (n=100), elevations in liver aminotransferases ≥ 3 × ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of > 3 x ULN) and increases in total bilirubin (≥ 2 x ULN) is a marker for potential serious hepatotoxicity. Elevations of AST or ALT associated with bosentan are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with bosentan. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly [see Dosage and Administration ( 2.1 , 2.4 )] . Discontinue bosentan if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN. Avoid initiation of bosentan in patients with elevated aminotransferases (> 3 x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning , Dosage and Administration ( 2.6 ), Use in Specific Populations ( 8.6 )] . In WHO Functional Class II patients, consider whether the benefits of bosentan are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses. Bosentan is only available through a restricted program under REMS [see Warnings and Precautions ( 5.2 )]. 5.2 Bosentan REMS Because of the risks of hepatotoxicity, bosentan is available only through a restricted program called the Bosentan REMS. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning, Warnings and Precautions ( 5.1 )] . Required components of the Bosentan REMS are: Healthcare professionals who prescribe bosentan must review the prescriber educational materials, enroll in the Bosentan REMS and comply with its requirements. Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly. To receive bosentan, all patients must understand the risks and benefits and complete a patient enrollment form with their prescriber. Pharmacies that dispense bosentan must enroll in the program and agree to comply with the Bosentan REMS requirements. Further information about bosentan and the Bosentan REMS is available at www.BosentanREMSProgram.com or 1-866-359-2612 5.3 Embryo-Fetal Toxicity Based on data from animal reproduction studies, bosentan may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. The available human data for endothelin receptor antagonists do not establish the presence or absence of major birth defects related to the use of bosentan. Advise females of reproductive potential about the potential risk to a fetus. Exclude pregnancy prior to bosentan treatment. Advise females of reproductive potential to use effective contraception prior to initiation of treatment with bosentan, during treatment, and for at least one month after the last dose. When pregnancy is detected, discontinue bosentan as soon as possible [see Dosage and Administration ( 2.1 ), Contraindications ( 4.1 ), Drug Interactions ( 7.2 ), Use in Specific Populations ( 8.1 , 8.3 )] . 5.4 Fluid Retention Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of bosentan and other endothelin receptor antagonists. In PAH clinical trials with bosentan, combined adverse events of fluid retention or edema were reported in 1.7% (placebo-corrected) of patients. In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting bosentan. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure. If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as bosentan or underlying heart failure and the possible need for treatment or discontinuation of bosentan [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.2 )] . 5.5 Pulmonary Veno-Occlusive Disease If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether bosentan should be discontinued. 5.6 Decreased Sperm Counts Decreased sperm counts have been observed in patients receiving bosentan. Preclinical data also suggest that bosentan, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis [see Adverse Reactions ( 6.1 ), Nonclinical Toxicology ( 13.1 )] . 5.7 Decreases in Hemoglobin and Hematocrit Treatment with bosentan can cause a dose-related decrease in hemoglobin and hematocrit. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. It is recommended that hemoglobin concentrations be checked after 1 and 3 months and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment [see Adverse Reactions ( 6.1 )] .
Who should not take Bosentan
Pregnancy ( 4.1 ) Use with Cyclosporine A ( 4.2 ) Use with Glyburide ( 4.3 ) Hypersensitivity ( 4.4 ) 4.1 Pregnancy Use of bosentan is contraindicated in females who are pregnant [see Boxed Warning, Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 )] . 4.2 Use with Cyclosporine A Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of bosentan and cyclosporine A is contraindicated [see Drug Interactions ( 7.1 )] . 4.3 Use with Glyburide An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and bosentan is contraindicated [see Drug Interactions ( 7.1 )] . 4.4 Hypersensitivity Bosentan is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash and angioedema [see Adverse Reactions ( 6.2 ), Description ( 11 )].
Overdose — what happens if you take too much
Bosentan has been given as a single dose of up to 2,400 mg in normal volunteers, or up to 2,000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1,000 mg twice daily of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. In the postmarketing period, there was one reported overdose of 10,000 mg of bosentan taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating and blurred vision. He recovered within 24 hours with blood pressure support. Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.
U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.
Interactions
Cytochrome P450: Coadministration of bosentan with drugs metabolized by CYP2C9 and CYP3A can increase exposure to bosentan and/or the coadministered drug ( 4.2 , 4.3 , 7.1 ). Hormonal contraceptives: bosentan use decreases contraceptive exposure and reduces effectiveness ( 7.2 ). 7.1 Cytochrome P450 Drug Interactions Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan [see Clinical Pharmacology ( 12.3 )] . Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with bosentan will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with bosentan is not recommended. Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when bosentan is co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, bosentan is not expected to increase the plasma concentrations of drugs metabolized by these enzymes. Figure 1 CYP3A induction-mediated effect of bosentan on other drugs F igure 2 Effect of other drugs on bosentan 7.2 Hormonal Contraceptives Hormonal contraceptives, including oral, injectable, transdermal and implantable forms, may not be reliable when bosentan is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking bosentan [see Use in Specific Populations ( 8.3 )] . An interaction study demonstrated that co-administration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects. Image Image
Storing Bosentan, and how long it keeps
Quoted from this product’s own FDA label. Storage belongs to the product and its device, not to the drug in general — a pen and a tablet of the same medicine are kept completely differently.
- “Divided dispersible tablets should be stored under the same conditions and used within 7 days.”
Drug class
How this class works, per Bosentan - StatPearls - NCBI Bookshelf.
May treat (source: NIH RxClass)
See how Bosentan ranks — best-rated endothelin receptor antagonist for:
Dosage forms
Tablet
The forms currently marketed in the U.S., per the FDA National Drug Code Directory.
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Frequently asked questions
- What does Bosentan treat?
- Bosentan (Bosentan) may be used to treat pulmonary hypertension, based on NIH RxClass drug-classification data (conditions a drug may treat — not a verbatim copy of the FDA-approved label). This is general reference, not medical advice.
- How does Bosentan work?
- Bosentan is a endothelin receptor antagonist. Endothelin receptor antagonists block endothelin-1, a natural substance that powerfully tightens blood vessels. By stopping it from acting on its receptors, these drugs let vessels relax and widen, lowering pressure in the lung arteries in conditions like pulmonary arterial hypertension.
- How is Bosentan rated?
- pharmaranks gives Bosentan a composite score of 3.3 out of 5, currently based on 1 weighted source (FDA regulatory recall-safety data weighted highest). See our methodology at /how-we-rate.
- Is there a coupon or discount for Bosentan?
- pharmaranks is an independent ratings site, not a pharmacy — we don't issue coupons or sell Bosentan. To pay less, Bosentan is already a generic — usually the lowest-cost version — so the main levers are comparing cash prices between pharmacies and using a pharmacy discount-card service. Prices vary by pharmacy, insurance, and location, so always confirm at the counter. This is general reference, not medical or financial advice.
- Who makes Bosentan?
- Bosentan is marketed by Zydus Pharms USA Inc. You can see Zydus Pharms USA Inc's full profile, rating, and other products on pharmaranks.
- Is Bosentan a brand-name or generic drug?
- Bosentan is a generic medication; its active ingredient is Bosentan. Generics contain the same active ingredient as the brand-name original and are usually lower cost.
- Is Bosentan available over the counter?
- No. Bosentan is a prescription (Rx) medication in the US — you need a prescription from a licensed clinician (in person or via telehealth); it isn't sold over the counter. For some conditions there are OTC alternatives — ask your pharmacist.
- What forms does Bosentan come in?
- Bosentan is currently marketed as tablet, per the FDA's National Drug Code Directory.
- What class of drug is Bosentan?
- Bosentan is classified as endothelin receptor antagonist, per the FDA's Established Pharmacologic Class.
- Is Bosentan FDA-registered?
- Bosentan is on record with the U.S. FDA under application number ANDA213981. You can verify this on its official FDA label.
- Has Bosentan been recalled by the FDA?
- Bosentan has no FDA recalls recorded under its own application in the openFDA enforcement database. Its recall-safety score reflects its manufacturer's overall recall record. This is general reference, not medical advice — check the FDA recall database for the latest alerts.
- Is Bosentan safe?
- There's no single safe-or-not verdict. pharmaranks gives Bosentan a recall-safety score of 66/100, based on its FDA recall history (no recalls under its own FDA application) — not an efficacy or side-effect rating. Review its FDA-label side effects and warnings before use, and always consult a licensed professional.
- What are the side effects of Bosentan?
- Bosentan's side effects are taken directly from its FDA label. From the label: The following important adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Boxed Warning, Warnings and Precautions ( 5.1 )] Embryo-fetal Toxicity [see Boxed Warning,… Both common and serious reactions are documented in full on this page. This is general reference from the FDA, not medical advice — always consult a professional.
Clinical content sourced from the FDA label via openFDA (U.S. FDA). View the FDA label on DailyMed → Provided for general reference only — not medical advice. Always consult a licensed professional and the current prescribing information.
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bosentan
66/100